The most common microdeletion syndrome is 22q11 deletion syndrome (22q11DS), also known as velocardiofacial syndrome or DiGeorge syndrome, which occurs in approximately 1 in every 4000 live births (Oskarsdottir, et al. (2004) Arch. Dis. Child 89:148-151). The syndrome is caused by a hemizygous deletion of a 1.5- to 3-megabase region within 22q11.2 that occurs either sporadically (85%-95% of cases) or as an inherited autosomal-dominant trait (5%-15% of cases) (Swillen, et al. (1998) Am. J. Med. Genet. 80:531-532). Cognitive defects occur in virtually all patients with 22q11DS. Children with 22q11.2DS have a high incidence of mild to moderate mental retardation and characteristic learning disabilities (Bearden, et al. (2001) J. Clin. Exp. Neuropsychol. 23:447-464; Eliez, et al. (2000) Eur. Child Adolesc. Psychiatry 9:109-114; Swillen, et al. (2000) Am. J. Med. Genet. 97:128-135). In approximately 30% of them schizophrenia or schizoaffective disorder develops during adolescence or early adulthood (Chow, et al. (2006) Schizophr. Res. 87:270-278; Pulver, et al. (1994) J. Nerv. Ment. Dis. 182:476-478).
The orthologous region of the human 22q11.2 locus lies on mouse chromosome 16. With one exception, all of the human genes in this region are represented in the mouse, although organized in a different order (Puech, et al. (1997) Proc. Natl. Acad. Sci. USA 94:14608-14613). Generation of mouse models that carry chromosomal deficiencies that are syntenic to the human 22q11.2 microdeletion have been reported (Lindsay, et al. (1999) Nature 401:379-383; Stark, et al. (2008) Nat. Genet 40:751-760; Merscher, et al. (2001) Cell 104:619-629).
Cognitive defects were demonstrated through the conditioned contextual fear paradigm in mouse models of 22q11.2DS (Df(16)1/+ mice) (Paylor, et al. (2001) Hum. Mol. Genet. 10:2645-2650), suggesting that hippocampal function is impaired by 22q11.2DS. Recent data support this idea by showing abnormal development of dendrites and dendritic spines in the hippocampal pyramidal neurons of another mouse model of 22811.2 DS (Mukai, et al. (2008) Nat. Neurosci. 11:1302-1310). Several reports have indicated that the gross morphology of the hippocampus is also affected in patients with 22q11.2DS (Chow, et al. (2002) Biol. Psychiatry 51:208-215; Debbane, et al. (2006) Neuropsychologia 44:2360-2365; Deboer, et al. (2007) Behav. Brain Funct. 3:54; Eliez, et al. (2001) Am. J. Psychiatry 158:447-453), and this observation positively correlates with the occurrence of cognitive impairment (Deboer, et al. (2007) supra).
Although these behavioral and morphological data point to the hippocampus as a brain region affected during 22q11DS, little is known about the consequences of 22q11.2 microdeletions on hippocampal synaptic plasticity, the activity-dependent changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD) that are believed to be important for information storage, fine-tuning of synaptic connections, and learning and memory (Martin, et al. (2000) Annu. Rev. Neurosci. 23:649-711; Milner, et al. (1998) Neuron 20:445-68). Moreover, it is not known whether changes in synaptic plasticity and behavior progress with age in a manner similar to the progression of symptoms in patients with 22q11.2DS. More importantly, nothing is known about the molecular mechanisms that are involved in synaptic plasticity and are affected by 22q11.2 microdeletions.